PROJECT SUMMARY/ABSTRACT Young women are highly vulnerable to HIV infection, particularly in endemic areas, with young adults making up 30-40% of new HIV infections globally. However, there is very little understanding of why there is discordant HIV infection susceptibility in adolescents versus adults. Furthermore, there is currently no established pre- clinical model to assess any prevention or therapeutic interventions with consideration of age. Here we aim to create the first nonhuman primate model of SIV infection and susceptibility in adolescents. We will assess the mucosal environment of the female genital tract (FGT) of adult compared to adolescent pigtail macaques (Macaca nemestrina). We will determine whether there are baseline differences across the menstrual cycle in adolescent versus adults, and will also determine whether adolescent pigtail macaques are more susceptible to SIV challenge. We will use state-of the art proteomic, microbiome, immunological and in vivo imaging techniques to take advantage of the in depth sampling (multiple tissue and longitudinal) capabilities of the nonhuman primate model. We will determine whether signatures associated with SIV/HIV susceptibility exist in adolescents compared to adults. We will also validate these studies using human cervicovaginal samples from adolescent and adult women. Furthermore, we will assess the mechanisms underlying an altered mucosal environment in adolescents. This will provide the first pre-clinical macaque model of HIV infection in adolescents that can delineate infection susceptibility, correlates of infection, and potential mechanisms underlying altered female genital tract in adolescents. These studies will be a critical advance in understanding of the increased susceptibility of adolescents to HIV infection, and provide the first model for testing interventions in young adults.